Infectious causes of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a serious chronic neurological disorder in which demyelination and inflammation occur in the white matter of the CNS. The findings of many epidemiological studies and a discordance of MS in monozygotic twins suggest that the disorder is acquired. The most likely cause is a virus because more than 90% of patients with MS have high concentrations of IgG, manifest as oligoclonal bands, in the brain and CSF. Most chronic inflammatory CNS disorders are infectious. More indirect evidence that MS is caused by a virus is the association of several viruses with demyelinating encephalomyelitis in human beings, and the induction of demyelination in animals infected with viruses in research. Nevertheless, no virus has been isolated from the brains of patients who had MS. Molecular analysis of IgG gene specificity in the brain and CSF of those with MS has shown features of an antigen-driven response: clonal amplification and extensive somatic mutations. A viral antigen against which the IgG in MS brain and CSF is directed might be identified.

Figure 1

MS brain plaque–periplaque white matter Direct immunofluorescence with a 1 to 20 dilution of antibody to human IgG conjugated to fluorescein isothiocyanate (green fluorescence) shows IgG deposition at the junction of plaque–periplaque white matter (middle arrow), in mononuclear cells (bottom arrow), and in normal white matter (top arrow). The antigen against which the IgG in MS brain and CSF is directed is unknown.

Figure 2

A proposed mechanism of demyelination by infection with Theiler's murine encephalomyelitis virus (TMEV) in mice TMEV is a highly cytolytic picornavirus. TMEV infection of oligodendrocytes is productive, resulting in cell lysis and liberation of more virions (bottom). By contrast, TMEV infection in macrophages is restricted, and results in apoptosis of macrophages. TMEV antigen is abundant in the cytoplasm of apoptotic macrophages (top centre). Small amounts of TMEV are liberated from persistently infected macrophages leading to infection of more macrophages as well as oligodendrocytes. A persistent CNS infection is established as virus spreads from macrophage to macrophage (across top). Virus released from macrophages can infect and kill more oligodendrocytes, thus adding to immunopathological destruction of myelin.